Allergic asthma stems from inappropriate immune responses to inhaled antigens. Thus, to prevent or treat allergic asthma, it is important to identify the cellular and molecular mechanisms that initially give rise to allergic sensitization, as well as the pathways that regulate allergic inflammation once it has begun. Accordingly, our laboratory uses mouse models of asthma in which the animals are senstized to a variety of inhaled allergens. For example, ovalbumin (OVA) is delivered to the airway together with various adjuvants. Such adjuvants include ligands of various toll-like receptors (TLRs), including lipopolysaccharide (LPS) and bacterial flagellin, as well as molecules that have protease activity. Pulmonary dendritic cells lining the airway epithelium take up OVA and migrate to draining thoracic lymph nodes to present allergen-derived peptides to naive T cells. These cells differentiate into T helper (Th)2 or Th17 cells that upon challenge with OVA produce IL-13 and IL-17, respectively. This in turn leads to airway eosinophilia and neutrophilia and gives rise to airway hyperresponsiveness (AHR). Th17 responses to inhaled allergens might be one means to distinguish severe asthma from less serious Th2-mediated diseases of the airway. IWe also study the differential impact of various environmental agents on pulmonary dendritic cell activation, and how these agents can act as adjuvants in the lung to promote allergic sensitization through the airway. We have found that many types of molecules can act as adjuvants, but can trigger distinct molecular pathways that give rise to different forms of asthma. For example, bacterial products, such as LPS and flagellin, promote allergic sensitization by activating the TNF pathway, whereas protease adjuvants act through the cytokine, IL-33. There are two major populations of resident lung dendritic cells. One population displays the cell surface molecule, CD103, whereas the other subset displays a different marker, CD11b. The latter can be divided into three distinct subsets by flow cytometery. We are comparing the functions of these four dendritic cell subsets following their enrichment by flow cytometry-based sorting and culture with antigen-specific, naive T cells. Finally, we are also studying how allergens interact with the airway epithelium and whether signals derived from the epithelium can modulate dendritic cells function. We hypothesize that this epithelial - dendritic cell cross talk is critical for orchestrating immune responses to inhaled allergens. Together, these approaches should allow us to identify and characterize cellular and molecular mechanisms that lead to allergic sensitization to inhaled allergens.